HEREDITARY HAEMOLYTIC ANAEMIAS BY DR. FATMA ALQAHTANI CONSULTANT HAEMATOLOGIST ENZYMOPATHIES GLUCOSE...

HEREDITARY HAEMOLYTIC ANAEMIAS

BY

DR. FATMA ALQAHTANI

CONSULTANT HAEMATOLOGIST

ENZYMOPATHIESENZYMOPATHIES

GLUCOSE - 6 – PHOSPHATE DEHYDROGENASE GLUCOSE - 6 – PHOSPHATE DEHYDROGENASE DEFICIENCYDEFICIENCY

HEREDITARY HAEMOLYTIC ANAEMIA

• METABOLIC DEFECTS: Deficiency of:

* Glucose-6-phosphate dehydrogenase * Pyruvate kinase * Triose phosphate isomerase * Pyrimidine-5-nucleotidase * Glutathione synthetase etc….


G-6-PD (MOL.WT. 50,000 – 55, 000)

• There are electrophoretic variants with normal activity.

• G6PD B is the most common normal type (historically).

• G6PD A is a fast moving non-deficient variant (common in Africa) and has no clinical significance.

• G6PD A should not be confused with the G6PD

deficient variant G6PD A- (seen in Nigeria).


Incidence and Geographical Distribution (Cont….)

• All variants other than B, A and A- are designated by geographical and trivial names.

• Over 400 variants are now known.

• High incidence in endemic malarious areas.

• It is thought to confer a selective protection against Plasmodium Falciprum Malaria


Incidence and Geographical Distribution

• G6PD ↓ is the most common metabolic disorder of red blood cells.

• Almost 200 million people are affected mainly in Tropical & Subtropical areas.

• Due to recent migrations G6PD ↓ has become widespread in many other areas.Very rare in indigenous population in Northern Europe20% in parts of:

Southern Europe Africa Asia

40% in certain areas of the Middle East


IN SOME HUMAN POPULATIONIN SOME HUMAN POPULATION

Country Frequency Most Commonin Males Variants

Greece 4 – 35 MediterraneanAthens-likeOrchomenosUnion-markham

Southern 2 – 22 MediterraneanItaly Sassari

Cagliary, Seatle-likeNigeria 18 – 25 A-

Thailand 3 – 14 Mahidol, Canton, Union, Hong Kong

Papua new 1-29 Markham, ManyGuinea Others


Genetics

• All variants result from point Mutations within theX-linked structural gene

↓Decreased activity

ordecreased stability

or both

• The genes controlling G6PD structure and synthesis are located on the X-chromosome very close to the genes of factor VIII genes and for color blindness.

• Males are the ones affected.• Females are more rarely affected in the homozygous state in particular.• Heterozygote females can have clinical manifistations (because of X-

chromosome inactivation).

G6PD q2-8


Clinical Features

• Clinical manifestation can be either• Acute (Haemolysis)

• Chronic (Haemolysis)

• Most affected individuals are asymptomatic until acute attack takes place. (In prevailing variants in various populations).

• Few show mild to moderate or severe chronic haemolytic anaemia. (In other rare variants).

Acute Haemolytic Anaemia- Under normal circumstances G6PD enzyme activity of 20% of normal

(even as low as 3%) is sufficient for normal red cell function.

- Triggering Factors• Fava Beans

• Infection

• Drugs


Clinical Features

Haemolytic Attack (Cont.)

• In general haemolysis is less severe with the African type (variant) A- than with the variant more prevalent in the Mediterranean, the Middle East and South East Asia.

(Sometimes it subsides even when the trigger is still present)

• Massive haemoglobinuria is seen most frequently in children with favism.

(Some degree of haemoglobinuria is always seen in an attack)

• Renal failure is very rare in children but not uncommon in adules.

• In some cases haemolysis can be self limiting.

(This is not necessary true for all drugs or for all variants)


Clinical Features

Haemolytic Attack (Cont.)

Favism

• Fava beans ingestion is not always followed by a haemolytic attack in G6PD↓ individuals.

• The offending agent may be the glucoside divicine or its aglycone isouramil.

• Those agents vary widely in different caltivars of vicia faba and with the way fava beans are consumed.

• Favism has been precipitated with fresh beans, dried beans, canned and frozen beans.

(It is commonest with fresh and raw beans)• Oxidative damage may depend on how much isouramil is released

by glycosidases present in the beans or in the intestinal tract of the consumer.


Features of Haemolytic Attack

Acute Phase• Sudden Onset

• Malaise, Prostration

• Pallor

• Fever

• Abdominal Pain

• Hypotension

• Dark Urine

• Jaundice

• Renal Failiure

Recovery Phase• Gradual But Rapid

• Urine Clears in Few Days

• Jaundice Clears in 1-2 weeks

O2

Drugs O2

(Other agents) Peroxidation Intra

• Bacteria OH of Vascular

• Divicine in Membrane Haemolysis

Fava Beans H2O2 Lipids

NADP GSH

Attachment Extra

Hb Denaturation To Vasc.

Heinz Bodies Membrane Haemolysis

NADPH GSSG

Mechanism of Haemolysis

in G6PD Deficiency

SOD

G6PD GSSGR

GSHPX


Characteristic Lab. Features of a Haemolytic Attack

Acute Phase

• Anaemia• Reticulocytosis• Heinz Bodies• G6PD deficient *• Leucocytosis• Haemoglobinaemia• Haemoglobinuria• Haptoglobin absent• Methaemalbuminaemia• Hyperbilirubinaemia• Raised Urea & Creatinine Levels

Recovery Phase

• Reticulocytes peak day 5-8• G6PD but rarely to normal range


Laboratory Diagnosis

• G6PD screening tests:

- Nitro blue tetrazolium (NBT) spot test- Fluorescent spot test- Cytochemical demonstration of G6PD↓

• Quantitative Assay:1. G-6-P + NADP + G6PD 6PGA + NADPH2. G{GA + NADP + 6pGD R5P + NADPH

Spectrophotometrically

Normal range at 37oCWHO G6PD IU/10 10 RBC = 3.6±0.6ICSH G6PD IU/1010 RBC = 2.5±0.5

NB: In acute attacks normal false screening test & assay results can be seen and a repeat between attacks is needed


Neonatal Jaundice (NNJ)

• Strong association is known between G6PD ↓ and NNJ.

• G6PD↓ can be considered the most common cause of NNJ in Nigeria and probably in other parts of the world.

• ½ of G6PD↓ babies do not develop NNJ.

Thus there have to be additional genetic, developmental or aquired factors interact with G6PD↓.

• Hyperbilirubinaemia develops usually late if compared with NNJ caused by Rh isoimmunization.

• Hyperbilirubinaemia is usually more than what expected in relation to the degree of haemolysis.

(This may be due to ↓ liver function in handling unconjugated bilirubin as a result of perhaps low G6PD in the hepatocytes).

G6PD Deficiency

Drugs which may cause haemolytic anaemia in subjects with G6PD deficiency

Drugs that can be given safely in therapeutic doses to subjects with G6PD deficiency without non-spherocytic haemolytic anaemia.

Antimalarials

Fansidar

Maloprim (contains dapsone)

Pamaquine

Pentaquine

Premaquine

? Chloroquine

Sulphonamides

Sulphamethoxazone

Some other sulphonamides

Sulphones

Dapsone

Thiazolesulphone

Other antibacterial compounds

Nitrofurans

Naladixic acid

Antihelminthicb-napthol

Sitophan

Miscellaneous

? Vitamin K

Napthalene (moth balls)

Methylene blue

Doxorubicin

Ascorbic acid

Aspirin

Colchicine

Isoniazid

Menadione

Phenytoin

Probenecid

Procainamide

Pyrimethanine

Quinidine

Quinine

Sulphamethoxypyridazine

Trimethoprim

? – there is some dispute with these compounds


TREATMENT OF ACUTE HAEMOLYTIC ANAEMIATREATMENT OF ACUTE HAEMOLYTIC ANAEMIA

• Withdrawal of the triggering agent or avoiding it.

• In pregnant & nursing women known to be heterozygous should avoid drugs with oxidant potential or use them cautiously.

• Phototherapy and exchange blood transusion is used in NNJ as in other cases of NNJ due to other causes.

• Transfusion therapy is unnecessary unless haemolytic episodes are complicated by concurrent arrest of erythropoiesis.


Chronic Haemolytic Anaemia

• It is rare

• Anaemia is normocytic & normochromic with:

- Reticulocytosis.

- No excess of spherocytes

• It is usually referred to as chronic non-spherocytic haemolytic anaemia (CNSHA)

• It is similar to CNSHA caused by other enzyme abnormalities e.g. PK↓

• There is a risk of acute haemolytic (AH) episodes triggered by the same agent that cause AH in G6PD.

• Bone marrow shows erythropoiesis without ineffective erythropoisis (Folic Acid can be used).


Chronic Haemolytic Anaemia (Cont….)

• There is no indication for a chronic blood transfusion regimen.

• Blood transfusion may be required in episodes of acute “aplastic” or hyperhaemolytic crisis.

• There is no evidence of selective red cell destruction in the spleen.

However, splenectomy has been beneficial in some cases.

HEREDITARY HAEMOLYTIC ANAEMIAS BY DR. FATMA ALQAHTANI CONSULTANT HAEMATOLOGIST ENZYMOPATHIES GLUCOSE...

Documents

Transcript of HEREDITARY HAEMOLYTIC ANAEMIAS BY DR. FATMA ALQAHTANI CONSULTANT HAEMATOLOGIST ENZYMOPATHIES GLUCOSE...